Baseline moderate-range albuminuria is associated with protection against severe COVID-19 pneumonia.

BACKGROUND: Diabetes mellitus is considered a leading contributor to severe coronavirus disease 2019 (COVID-19). AIM: To characterize differences between hospitalized diabetic patients with vs without COVID-19, and parameters associated with COVID-19 severity for prediction. METHODS: This case-control study included 209 patients with type 2 diabetic mellitus hospitalized at the Galilee Medical Center (Nahariya, Israel) and recruited between September 2020 and May 2021, 65 patients with COVID-19 infection in dedicated wards and 144 COVID-19-negative patients in internal medicine wards hospitalized due to other reasons. Clinical parameters - including age, type of antiglycemic medications, presence of retinopathy, smoking history, body mass index (BMI), glycosylated hemoglobin, maximum neutrophil:lymphocyte ratio (NLRmax), C-reactive protein (CRP), estimated glomerular filtration rate (eGFR), and albumin (blood and urine) - were compared between the two primary patient groups, and then between COVID-19-negative patients hospitalized due to infectious vs non-infectious disease. Finally, we explored which parameters were associated with severe COVID-19 pneumonia. RESULTS: COVID-19-negative patients were older (63.9 ± 9.9 vs 59.8 ± 9.2, P = 0.005), and had longer duration of diabetes (P = 0.031), lower eGFR (P = 0.033), higher albumin (P = 0.026), lower CRP (P < 0.001), greater smoking prevalence (P < 0.001), and more baseline albuminuria (54.9% vs 30.8%, P = 0.005) at admission; 70% of COVID-19 patients with albuminuria had moderate-range albuminuria (albumin:creatinine 30-300 mg/g). Most of the patients with albuminuria had chronic kidney disease stage II (CKD II). Oral antiglycemic therapies were not significantly different between the two groups. Multivariable logistic regression showed that higher BMI was significantly associated with severe COVID-19 (OR 1.24, 95%CI: 1.01-1.53, P = 0.04), as was higher NLRmax (OR 1.2, 95%CI: 1.06-1.37, P = 0.005). Surprisingly, pre-hospitalization albuminuria, mostly moderate-range, was associated with reduced risk (OR 0.09, 95%CI: 0.01-0.62, P = 0.015). Moderate-range albuminuria was not associated with bacterial infections. CONCLUSION: Moderate-range albuminuria in COVID-19-positive diabetic patients with CKD II is associated with less severe COVID-19. Further studies should explore this potential biomarker for risk of COVID-19-related deterioration and early interventions.

Pre-infection 25-hydroxyvitamin D3 levels and association with severity of COVID-19 illness.

OBJECTIVE: Studies have demonstrated a potential correlation between low vitamin D status and both an increased risk of infection with SARS-CoV-2 and poorer clinical outcomes. This retrospective study examines if, and to what degree, a relationship exists between pre-infection serum 25-hydroxyvitamin D (25(OH)D) level and disease severity and mortality due to SARS-CoV-2. PARTICIPANTS: The records of individuals admitted between April 7th, 2020 and February 4th, 2021 to the Galilee Medical Center (GMC) in Nahariya, Israel, with positive polymerase chain reaction (PCR) tests for SARS-CoV-2 (COVID-19) were searched for historical 25(OH)D levels measured 14 to 730 days prior to the positive PCR test. DESIGN: Patients admitted to GMC with COVID-19 were categorized according to disease severity and level of 25(OH)D. An association between pre-infection 25(OH)D levels, divided between four categories (deficient, insufficient, adequate, and high-normal), and COVID-19 severity was ascertained utilizing a multivariable regression analysis. To isolate the possible influence of the sinusoidal pattern of seasonal 25(OH)D changes throughout the year, a cosinor model was used. RESULTS: Of 1176 patients admitted, 253 had records of a 25(OH)D level prior to COVID-19 infection. A lower vitamin D status was more common in patients with the severe or critical disease (<20 ng/mL [87.4%]) than in individuals with mild or moderate disease (<20 ng/mL [34.3%] p < 0.001). Patients with vitamin D deficiency (<20 ng/mL) were 14 times more likely to have severe or critical disease than patients with 25(OH)D ≥40 ng/mL (odds ratio [OR], 14; 95% confidence interval [CI], 4 to 51; p < 0.001). CONCLUSIONS: Among hospitalized COVID-19 patients, pre-infection deficiency of vitamin D was associated with increased disease severity and mortality.

Subclinical hypothyroidism or isolated high TSH in hospitalized patients with chronic heart-failure and chronic renal-failure.

Sub-clinical hypothyroidism (SCH) is common in heart failure (HF) and advanced renal failure (RF), but it is unclear whether there is a thyroid disease or a transient increase in TSH level. This is a retrospective study of hospitalized patients in medical departments. All patients with SCH and a TSH level up to less than 12 mIU/L were identified. Those who had at least one recurring admission within at least 6 months were included. A change in thyroid function during the last re-admission was determined and classified as an improvement, no change, or worsening of thyroid function. Overall, 126 cases of SCH met the inclusion criteria for re-admission. Analysis of the most recent hospitalization showed that in 100 (79.4%) patients thyroid function improved, in 15 (11.9%) patients thyroid function remained unchanged and only in 11 (8.7%) patients did thyroid function worsen. In most cases, worsening of hypothyroidism was determined by initiation of a low dose levothyroxine treatment. Of the 126 participants, 43 (34.1%) and 22 (17.5%) had a diagnosis of HF and RF (CKD stages 4 and 5), respectively. There was no association between HF or advanced RF and worsening of SCH. No association was found between worsening of hypothyroidism and gender, age, TSH, or creatinine levels in the first hospitalization. A borderline association between elevated CRP levels at first hospitalization and hypothyroidism worsening was found (p = 0.066). Mildly elevated TSH in hospitalized patients with HF and advanced RF is transient and most probably not related to thyroid disease and not associated with age or gender.

Forty-One Plant Extracts Screened for Dual Antidiabetic and Antioxidant Functions: Evaluating the Types of Correlation between -Amylase Inhibition and Free Radical Scavenging.

Dysregulation of glucose homeostasis followed by chronic hyperglycemia is a hallmark of diabetes mellitus (DM), a disease spreading as a worldwide pandemic for which there is no satisfactory dietary treatment or cure. The development of glucose-controlling drugs that can prevent complications of DM, such as hyperglycemia and oxidative stress, which contribute to the impairment of the key physiological processes in the body, is of grave importance. In pursuit of this goal, this study screened 41 plant extracts for their antidiabetic and antioxidant activities by employing assays to test for α-amylase inhibition and free radical scavenging activity (FRSA) and by measuring glucose uptake in L6-GLUT4myc cells. While extracts of Rhus coriaria, Punica granatum, Olea europaea, Pelargonium spp., Stevia rebaudiana, and Petroselinum crispum demonstrated significant α-amylase inhibition, the extracts of Rhus coriaria and Pelargonium spp. also demonstrated increased FRSA, and the extract of Rhus coriaria stimulated glucose uptake. These natural extracts, which are believed to have fewer side effects because they are prepared from edible plants, interfere with the process in the small intestine that breaks down dietary carbohydrates into monosaccharide and disaccharide derivatives, and thereby suppress increases in diet-induced blood glucose; hence, they may have clinical value for type 2 diabetes management. The Pelargonium spp. and Rhus coriaria extracts demonstrated the highest antidiabetic and antioxidant activities. Both plants may offer valuable medical benefits, especially because they can be taken as dietary supplements by patients with diabetes and can serve as sources of new, natural-based antidiabetic drug candidates. The enhancement of cellular glucose uptake stimulated by Rhus coriaria extract could lead to the development of clinical applications that regulate blood glucose levels from within the circulatory system. Isolating bioactive substances from these plant extracts and testing them in diabetic mice will significantly advance the development of natural drugs that have both antidiabetic and free radical-scavenging properties, likely with lesser side effects.

The significance of high thyroxine in hospitalized patients with low thyroid-stimulating hormone.

PURPOSE: There is scarce data about the interpretation of high thyroid hormone levels in hospitalized patients. We wished to investigate the significance of high thyroxine (T4) in hospitalized patients with low TSH. METHODS: We conducted a retrospective study of data from patients in nonsurgical departments. Three groups of random patients with low TSH were defined and compared: 123 patients with only high FT4 levels (T4 group), 82 with high FT3 levels with or without high FT4 level (T3 group), and 119 with low FT3 and FT4 level in the lower half of the norm and below (NTIS group). RESULTS: The primary cause of admission in the T4 and NTIS groups was infectious disease, 20.3% and 40.3%, respectively; while in the T3 group it was cardiovascular disease (31.7%). The T4 group but not T3 group had epidemiological and clinical characteristics similar to the NTIS group. The T4 group had a significant correlation between increased CRP levels and decreased FT3 (r = 0.366, p < 0.001) similar to the NTIS group. The T3 group had a borderline correlation between increased FT3 and FT4 levels (r = 0.208, p = 0.061) but the T4 group did not. CONCLUSIONS: The combination of low TSH and high FT4 levels in hospitalized patient is usually caused by nonthyroidal illness combined with drug effects. This thyroid function disturbance is common in hospitalized patients and if the FT3 level is below the middle of the norm, treatment is probably unnecessary.

Low brain-derived neurotrophic factor protein levels and single-nucleotide polymorphism Val66Met are associated with peripheral neuropathy in type II diabetic patients.

BACKGROUND: Studies by our group demonstrated brain-derived neurotrophic factor (BDNF) levels in blood and BDNF-Val66met-SNP as potential biomarkers in chemotherapy-induced peripheral neuropathy. Here, we evaluate symptoms of peripheral neuropathy (PN) and depression in patients with type II diabetes mellitus in search of an association with serum BDNF levels and the Val66Met-SNP. METHODS: In total, 90 patients enrolled in the study; 23 (25.6%) had known PN, as determined by nerve conduction studies (NCS-PN), and 67 (74.4%) were not diagnosed with PN (U-PN). PN symptoms were assessed and graded in these groups using the total neuropathy score (TNSr) and DN4 scales. Small nerve fiber testing of sensitivity thresholds to cold, warm and hot pain signals was performed using the Q-sense device. Depression was assessed using the PHQ9 questionnaire. BDNF protein levels and Val66Met-SNP were determined with ELISA and Sanger sequencing, respectively. RESULTS: NCS-PN patients showed lower serum BDNF levels alongside significantly higher TNSr, DN4 and PHQ9 scores and lower hot pain sensitivity thresholds as compared to U-PN patients. Patients with Met-BDNF-SNP showed increased TNSr scores and lower hot pain sensitivity thresholds as compared to patients with Val-BDNF-SNP. Depression showed a weaker correlation with sensitivity thresholds to hot pain signals as compared to TNSr and DN4 scores. CONCLUSIONS: Diminished peripheral BDNF resources and Met-BDNF-SNP genotype are associated with augmented symptoms of PN in patients with type II diabetes mellitus. Sensitivity thresholds to hot pain signals may be less influenced by depression and possibly more accurately detect PN symptoms in diabetic patients.

Neutrophil-to-lymphocyte ratio and red blood cell distribution width as predictors of microalbuminuria in type 2 diabetes.

BACKGROUND AND AIM: Chronic inflammation has an important role in the development and progression of type 2 diabetes through immunologic inflammatory mechanisms. Simple new inexpensive inflammatory markers may contribute to the detection of microalbuminuria. Aim of our study is to evaluate the predictive value of neutrophil-to-lymphocyte ratio (NLR), mean platelet volume (MPV), and red blood cell distribution width (RDW) for microalbuminuria in type 2 diabetic patients for possible application as prognostic factors for the prediction of microalbuminuria and the progression of disease in patients with diabetes. METHODS: A total of 168 patients with type 2 diabetes mellitus were classified into gender- and BMI-matched three groups according to hemoglobin A1c and microalbuminuria: Group A: 53 patients with controlled diabetes, Group B: 57 patients with uncontrolled diabetes, both without microalbuminuria, and Group C: 58 patients with uncontrolled diabetes with microalbuminuria. Levels of NLR, MPV, and RDW between the study groups were examined and compared. RESULTS: A significant difference in NLR was found between Group C and groups A and B (P < .001, P = .005, respectively). A statistically significant difference in RDW was found between groups B and C (P = .014). Receiver operating characteristic curve analysis of inflammatory markers and microalbuminuria prediction showed an area under curve (AUC) of 0.675 for NLR (CI 0.58-0.76, P < .001) and 0.614 for RDW (CI 0.52-0.70, P = .013). NLR value of 2.54 has 39.7% sensitivity, 78.8% specificity, and 45% positive predictive value (PPV). RDW value of 14.44 has 37.9% sensitivity, 76% specificity, and 41.5% PPV. CONCLUSIONS: Neutrophil-to-lymphocyte ratio and RDW have PPV for microalbuminuria in diabetic patients.

Is routine measurement of TSH in hospitalized patients necessary?

TSH routine testing in hospitalized patients has low efficacy, but may be beneficial in a selected subgroup of patients. Our aim was to evaluate the efficacy of routine thyroid function tests among patients admitted to internal medicine departments. It is a retrospective study. A randomly selected cohort of hospitalized patients with abnormal thyroid-stimulating hormone (TSH) blood tests drawn as part of admission protocol. Patient data were collected from the electronic medical files and analyzed for its efficacy. TSH as a screening test was proven unnecessary in 75% (174) of the study population. Leading causes were non-thyroidal illness syndrome, drugs affecting the test results and subclinical disorders. TSH testing was found to be clinically helpful in only 9 patients; however, all of them had other clinical need for TSH testing. We found a clinically abnormal TSH in 20 patients, hypothyroidism in 11 patients and thyrotoxicosis in 9 patients. Low efficacy ascribed to TSH screening test by this study correlates with recent recommendations that indicate TSH screening in admitted patients only with accompanying clinical suspicion. Most probably, the majority of patients found by screening to have thyrotoxicosis have non-thyroidal illness or drug effects so the threshold for FT4 to diagnose overt thyrotoxicosis should be higher than that in ambulatory patients. In elderly patients, clinically relevant TSH disturbances are more frequent and are harder to diagnose, therefore, TSH screening in this group of patients might be beneficial.

[THE CLINICAL APPROACH TO DIAGNOSIS AND TREATMENT OF HYPOTHYROIDISM].

INTRODUCTION: Hypothyroidism is the most frequent endocrinologic disorder after diabetes. It is caused by the insufficient production of thyroid hormones Thyroxine (T4) and Triiodothyronine (T3). T4 is the main hormone that is accumulated in the thyroid gland, while T3 is the active hormone that is produced from T4 in the peripheral tissues. More than 99% of the patients have primary hypothyroidism which is due to thyroid disorder mainly Hashimoto's thyroiditis or iatrogenic. Hypothyroidism is divided into sub-clinical when T4 is in the normal range and overt when it is low and usually the TSH level is higher than 10 mIU\L. The diagnosis is based on blood tests, because the signs and symptoms are neither specific nor sensitive. In the elderly, the upper limit of normal TSH level is higher than that reported by the laboratory in Israel and in healthy young it is lower. TSH is the most sensitive tool for screening, diagnosis and treatment follow-up when the pituitary is normal. The drug of choice in hypothyroidism is Levothyroxine (T4 salt) which is very effective, well tolerated and inexpensive.

The effect of infliximab and timing of vaccination on the humoral response to influenza vaccination in patients with rheumatoid arthritis and ankylosing spondylitis.

OBJECTIVES: To assess the effect of the timing of vaccination in relation to administration of infliximab on the efficacy and safety of influenza vaccine in patients with rheumatoid arthritis (RA) and ankylosing spondylitis (AS). METHODS: The study population comprised 38 patients treated with infliximab at a mean dosage of 3 mg/kg (20 RA patients; 18 AS patients; 23 RA controls (treated with disease modifying antirheumatic drugs other than anti-tumor necrosis factor-alpha; and 17 healthy controls). Split-virion inactivated vaccine containing 15 mug hemagglutinin/dose of each of A/New Caledionan/20/1999 (H1N1), A/Wisconsin/67/2005 (H3N2), and B/Malaysia/2506/2004 (M) was used. Patients treated with infliximab were divided into 2 groups: 22 were vaccinated on the day of administration of infliximab, while 16 received the vaccine 3 weeks after infliximab. Baseline and 4- to 6-week clinical assessment of disease activity included erythrocyte sedimentation rate and C-reactive protein for all patients, the 28-joint disease-activity score for RA patients, and Bath Ankylosing Spondylitis Disease Activity Index for AS patients. Hemagglutination inhibition (HI) antibodies were tested by a standard World Health Organization procedure. Response was defined as >or=4-fold rise in HI antibodies 4 to 6 weeks after vaccination, or seroconversion in patients with a nonprotective baseline level of antibodies (<1/40). Geometric mean titers (GMT) were calculated to assess the immunity of the whole group. RESULTS: At baseline, RA patients and controls had similar occurrence of protective levels of HI antibodies and GMT, while AS patients had lower levels reflecting lower rates of previous vaccination. Four weeks after vaccination, a significant and similar increase in GMT for each antigen was observed in all groups (P < 0.004) except in the RA-infliximab group, vaccinated 3 weeks after administration of infliximab, in whom the increase in GMT was not significant for H1N1 (P = 0.12) and H3 (P = 0.06). AS patients demonstrated an increase in GMT, independently of the time of vaccination. The percentage of responders was similar in all groups. The response was not affected by variables such as age, gender, methotrexate, or prednisone use. Parameters of disease activity remained unchanged. No adverse effects other than injection site pain were recorded. CONCLUSIONS: Influenza virus vaccine generated a good humoral response in RA and AS patients treated with infliximab.

Automated system to detect low-grade underlying inflammatory profile: Gaucher disease as a model.

Patients with Gaucher disease, perhaps due to chronic storage of glycolipids, apparently harbor a subclinical or underlying inflammation. Quantification of a baseline inflammatory profile in patients with Gaucher disease is more impressive when compared with that of matched healthy controls in a systematic, automated fashion. A mean of 16 healthy controls was generated for each of 50 patients with Gaucher disease by applying variables relating to potential for inflammatory features, for example, atherothrombotic risk factors. Relative to matched controls, male patients with Gaucher disease had significant elevations in fibrinogen (312 +/- 61 vs. 244 +/- 21 mg/dl; P = 0.002), accelerated erythrocyte sedimentation rate (ESR) (21.5 +/- 16.1 vs. 7.0 +/- 1.4 mm/H; P = 0.004), and elevated high-sensitivity C-reactive protein (hs-CRP) (1.4 +/- 2.4 vs. 0.9 +/- 1.6 mg/l; P = 0.026). Comparison of female patients versus controls revealed significant elevations in fibrinogen (337 +/- 81 vs. 273 +/- 19 mg/dl; P < 0.0005) and accelerated erythrocyte sedimentation rate (33.1 +/- 22.2 vs. 15.6 +/- 3.1 mm/H; P < 0.0005). Enzyme replacement therapy for Gaucher disease did not affect these values. Comparison with the matched healthy controls highlights the true low-grade inflammatory profile in Gaucher disease. By employing information from well-matched controls, even low-grade inflammatory conditions that may have otherwise been considered "within normal limits" can be teased out. This approach is not disease-specific and can be easily applied to any acute or subacute inflammatory disease/condition.

Rheological determinants in patients with Gaucher disease and internal inflammation.

The purpose of this study was to determine whether the inflammatory response in patients with Gaucher disease (GD) is accompanied by enhanced adhesiveness/aggregation of both red and white blood cells. Sixty patients with GD and matched controls were included. The degree of erythrocyte and leukocyte adhesiveness/aggregation was determined by using a simple slide test and image analysis. Patients with GD had significantly elevated concentrations of fibrinogen (328 vs. 262 mg/dl, P < 0.0001) and accelerated erythrocyte sedimentation rates (27 vs. 13 mm/H, P < 0.005). This was accompanied by a significantly enhanced degree of erythrocyte (75 vs. 85, P < 0.0001) and leukocyte (3.5 vs. 1.3, P < 0.002) adhesiveness/aggregation. The low-grade, smoldering, and subclinical internal inflammation in individuals with GD is accompanied by an increased degree of erythrocyte and leukocyte adhesiveness/aggregation. These findings might have rheological consequences in terms of microcirculatory slow flow and tissue hypoxemia.